The present invention relates to a therapeutic agent for treating a patient of diabetes or hyperlipemia, more particularly, a therapeutic agent for treating a patient of diabetes or hyperlipemia which comprises a neurotrophic factor as an active ingredient.
Recently, the number of patients afflicted with degenerative diseases, especially diabetes mellitus, diabetic complications, or hyperlipemia, has been increased, due to an improvement in a living standard, and/or change of the dietary life into the Western style, or increase in lack of exercise. Hyperlipemia is a very important underlining disease, which causes arteriosclerosis, and as a result, further leads to ischemic heart diseases, and occasionally, may lead to the onset of acute pancreatitis. In addition, there is a tendency of increasing numbers of patients afflicted with these diseases in the young generation.
Diabetes is classified into insulin dependent diabetes mellitus (type I, IDDM) and non insulin dependent diabetes mellitus (type II, NIDDM), and more than 90% of patients of diabetes mellitus are patients afflicted with the latter one. Insulin injections are used for the treatment of IDDM, and an oral antidiabetic agent such as sulfonyl urea or a biguanide compound is employed for the treatment of NIDDM, together with exercise therapy or dietary therapy (cf. Today""s Therapy 1993, supervised by Shigeaki HINOHARA, Masakazu ABE, published by IGAKU SHOIN, pages 494-498). These drugs are commonly used in order to control the blood glucose level, which is the most important indicator in the treatment of diabetes, but their effects are not sufficient enough, and in fact, continuous hyperglycemia causes various diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiovascular diseases, or delay in healing or ulceration of wound. Besides various risk factors such as an acute hypoglycemia by insulin injection, prolonged hypoglycemia by an insulin secretagogue, sulfonylurea, lactic acidosis by anaerobic inhibitor of glycolysis, biguanide, affect the quality of life of patients afflicted with diabetes.
In addition, type II diabetes mellitus is often accompanied by hyperlipemia, and an unusual high level of cholesterol or triglyceride (i.e., more than 220 mg/dl of total cholesterol, or more than 150 mg/ml of triglyceride) is a risk factor to cause arteriosclerosis including myocardial infarction, or acute pancreatitis, and hence, it is a target to be treated by medication. In the treatment of hypercholesterolemia, a HMG-CoA reductase inhibitor (e.g., pravastatin, simvastatin), or cholestyramine inhibiting enterohepatic circulation of bile acid is prescribed, and in the treatment of hypertriglyceridemia, a fibrate agent or a nicotinic acid agent having moderate effects is mainly prescribed (cf. Today""s Therapy 1993, supervised by Shigeaki HINOHARA, Masakazu ABE, published by IGAKU SHOIN, pp. 515-517; Shoichi BANNO et al, Chiryo (treatment), vol. 78, the extra number, Guideline for Standard Receipt 96, pp. 1060-1066). However, an essential drug therapy for hyperlipemia has not been established yet, and diabetic complications caused by abnormal continuous blood lipid level, such as arteriosclerosis, ischemic heart diseases, are one of the main causes for death in the developed countries. HMG-CoA reductase inhibitors can be orally administered, and have excellent pharmacological activities, but they also show an adverse serious side effect, rhabdomyolysis, in patients of hepatic dysfunction or renal dysfunction.
Type II diabetes mellitus is often accompanied by obesity. Obesity is considered to relate to hypertension, or to the vascular disorders of the brain and the heart, in the epidemiology research, and obesity is mainly treated by a dietary therapy or an exercise therapy. However, in case of advanced obesity or in case that exercise is not available, a surgery (stomach contraction operation) or a medication (central nervous system stimulators such as an adrenergic drug, a serotonin-type drug, a digestive absorption inhibitor) have been employed, but such therapies are still in the trial stage, and an essential drug therapy for obesity has not been established yet (cf. Obesity, Nippon-Rinsho, vol. 53, 1995, special issue, issued on Jun. 22, 1995, pp. 481-492, Nippon Rinsho Co.).
As mentioned above, type II diabetes mellitus, hyperlipemia and obesity are extremely deeply related each other, however, in order to improve each condition, merely a symptomatic therapy or a symptomatic medication has been employed. However, a therapy with a controlled diet or a multiple medication is not preferable because these methods give the patients more burdens.
On the other hand, neurotrophic factors are a generic name of proteins, which are provided from target cells or neurons and glia cells-Schwann cells in the living body, and show activities to maintain the survival and differentiation of neurons, and are classified into many types according to the kinds of nerves or receptors to function. Among them, proteins being known as neurotrophins have high structural homology with each other, and form a family thereof. The typical examples thereof are NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin 3), NT-4/5, etc., and they are known to act as a specific ligand of receptors, which are the products of P-75 and trk genes (cf. Takeshi NONOMURA, Hiroshi HATANAKA; Jikken Igaku vol. 13, p. 376 (1995)). Neurotrophic factors such as NGF, BDNF, etc. have been studied on the clinical utility thereof as a therapeutic agent for treating a patient of neurodegenerative diseases such as Alzheimer""s disease, diabetic neuropathy, ALS, etc., but an activity of reducing blood glucose level in the living body in the state of hyperglycemia or an activity on fat metabolism disorder such as hyperlipemia has not been reported yet. For example, A. P. Mizisin et al. Society for Neuroscience, vol. 21, p. 1535 (1995) discloses the pharmacological activity of BDNF on diabetic peripheral neuropathy, but this literature merely suggests the possible pharmacological activity of BDNF on neuropathy based on the finding that BDNF improves the reduction of motor nerve conduction velocity in vivo, and said literature does not suggest the ameliorating activity of common pathologies of diabetes such as hyperglycemia, or insulin resistance causing hyperglycemia. Japanese Patent Publication No. 7-507053 (WO 93/15608) discloses an effect on diabetic retinopathy as a pharmacological activity of BDNF, but said patent application is related to neuropathy in retina. Besides, activities on hyperlipemia or obesity, which is fat metabolism disorder, and on hyperinsulinemia, which is endocrinopathy, have not been reported as an activity of neurotrophic factors. In addition, hitherto, the hypoglycemic activity of other neurotrophic factors has not been known yet, as mentioned below. That is, Brain Research vol. 634, p. 7-12 (1994) discloses the peripheral dysensthesia improving activity of NGF in streptozotocin-induced diabetic model rats, but its hypoglycemic activity is not disclosed therein. Japanese Patent Publication No. 5-161493 (WO 91/3659) discloses the utility of NT-3 in the case of peripheral neuropathy including diabetic neuropathy, but its hypoglycemic activity is not disclosed therein. In addition, Japanese Patent Publication No. 7-509600 (WO 93/25684) and Japanese Patent Publication No. 6-501617 (WO 92/5254) disclose the utility of NT-4 in the treatment of peripheral neuropathy including diabetic neuropathy, but its hypoglycemic activity is not disclosed therein. However, the hypoglycemic activity of CNTF is disclosed (cf. Cytokine vol. 7, p. 150-156 (1995); Cytokine vol. 8, p. 784-793 (1996)), but said literatures merely indicate that the blood glucose level of the normal mice is decreased from the normal level (from about 100 mg/dl to about 80 mg/dl) by the intravenous injection of CNTF at the dose of 10 xcexcg/kg, and the normal blood glucose level is decreased by transplantation of CNTF producing cells. This temporary decrease into the blood glucose level less than the normal level is caused by Cytokine IL-1-like effect as disclosed in said literature, which is considered to be substantially different from the effects of neurotrophic factors remarkably reducing the hyperglycemia in type II diabetic animal models, which is the essence of the present invention.
An object of the present invention is to provide a novel therapeutic agent for treating a patient of diabetes which can safely control the blood glucose level of the diabetic patient, and also to provide a novel therapeutic agent for treating a patient of hyperlipemia which can safely control the blood lipid level of the hyperlipemia patient. Especially, the present invention provides a therapeutic agent for treating a patient of diabetes which can cure type II diabetic mellitus accompanied by hyperglycemia caused by dysfunction of insulin activity, insulin resistance, reduction or failure of insulin secretion, glucose toxicity, hyperlipemia, obesity or hyperinsulinemia.
The present inventors have intensively studied the effects of neurotrophic factors which are peripherally administered to various diabetic animal models, and have found that the blood glucose level and the blood lipid level of spontaneously diabetic mice accompanied by hyperglycemia, obesity, insulin resistance, and hyperinsulinemia (one of type II diabetic model animals, C57db/db mouse, Hitoshi ISHIDA et al., Saishin Igaku, vol. 48, p. 34 (1993)) can be reduced by administration of BDNF. Based on these findings further studies have been done, and as a result, the present invention has been accomplished.
That is, the present invention relates to the following medicaments.
(1) A therapeutic agent for treatment of a diabetes or a hyperlipemia, which comprises a neurotrophic factor as an active ingredient.
(2) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a member selected from a neurotrophin family.
(3) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a ligand of a trk or a p75 receptor.
(4) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a ligand of a trkB or a trkC receptor.
(5) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a brain-derived neurotrophic factor (BDNF).
(6) A therapeutic agent according to the above (1), wherein the neurotrophic factor is an NGF.
(7) A therapeutic agent according to the above (1), wherein the neurotrophic factor is an NT-3 or an NT-4/5.
(8) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a CNTF.
(9) A therapeutic agent according to the above (1), wherein the neurotrophic factor is a GDNF.
(10) A therapeutic agent according to the above (1), wherein the neurotrophic factor is an HGF.
(11) A therapeutic agent according to any one of the above (1) to (10), wherein the diabetes is a non insulin dependent diabetes mellitus (type II, NIDDM).
(12) A therapeutic agent according to any one of the above (1) to (10), wherein the diabetes is a non insulin dependent diabetes mellitus, accompanied by a hyperglycemia, a hyperinsulinemia, a hyperlipemia, and/or an obesity.
(13) A therapeutic agent according to any one of the above (1) to (12), which exhibits its pharmacological activity through a humoral biologically active substance induced by a neurotrophic factor.
(14) A therapeutic agent for treatment of a hyperinsulinemia, which comprises a neurotrophic factor as an active ingredient.
(15) A therapeutic agent according to the above (14), wherein the hyperinsulinemia is accompanied by a Syndrome X, a Deadly quartet, or a visceral fat syndrome.
(16) A therapeutic agent for treatment of a hyperlipemia according to any one of the above (1)-(10), which is employed in the treatment of a hyperlipemia associating a diabetes.
(17) A therapeutic agent for treatment of a hyperlipemia according to any one of the above (1) to (10), which is employed in the treatment of a hyperlipemia associating an obesity.
(18) A therapeutic agent for treatment of a hyperlipemia according to any one of the above (1)-(10), which is the agent for treatment of a hypertriglyceridemia.